(1) Field of the Invention
The present invention relates, in general, to an extract of Nelumbinis Semen (Nelumbo nucifera) having a therapeutic effect on depression, a method of preparing the extract, and a pharmaceutical composition and a health food comprising the extract. More particularly, the present invention relates to a Nelumbinis Semen extract obtained by extracting Nelumbinis Semen with an alcohol or an alcohol solution and concentrating and drying the resulting extract, a method of preparing the Nelumbinis Semen extract, and a pharmaceutical composition and a health food which comprise the Nelumbinis Semen extract as an effective component.
(2) Description of the Related Art
Mental damage occurring in the complicated modern society is, contrary to in the past, mostly caused by weak but prolonged and repeated stress from usual activities rather than large psychological impact or stimuli. Such stress is difficult to be recognized by patients and easily overlooked during hospital visits by patients, and thus accumulates, causing individuals to suffer from depression.
Depression is an emotional pathological phenomenon occurring regardless of objective situations. Emotional symptoms of depression include depressed behavior during all activities, anhedonia (loss of interest or pleasure), diminished mental capacity, pessimism, poor self-esteem, and suicidal thoughts that occasionally lead to suicide attempts. Physical symptoms of depression include decreased appetite, insomnia, constipation, diminished sexual desire, reduced immune functions, and patients' susceptibility to diseases due to the reduced immune function.
There has been so far no theory that perfectly explains the mechanism causing depression and the action mechanism of antidepressants for treating depression. However, for many years, the prevailing hypothesis is that depression is caused by an absolute or relative deficiency of monoamine neurotransmitters in synapses of the central nervous system, such as serotonin, norepinephrin and dopamine. In this regard, all antidepressants have pharmaceutical action to increase concentrations of neurotransmitters in central serotonin or noradrenaline synapses.
Antidepressants are divided into three major types according to the mechanism involving increasing the neurotransmitter levels: tricyclic antidepressants (TCA); monoamine oxidase inhibitors (MAOI); and selective serotonin reuptake inhibitors (SSRI).
Monoamine oxidase inhibitors, such as phenelzine developed a relatively long time ago, have a severe adverse effect of inducing heart diseases, and thus, have not been widely used recently. Tricyclic antidepressants such as imipramine also have anticholinergic, sedative, and other side effects related to the cardiovascular system. Thus, recent research focuses on the development of therapeutic agents against depression using selective serotonin (5-hydroxytryptamine, or 5-HT) reuptake inhibitors (hereinafter, referred to simply as “SSRI”) as antidepressants with fewer side effects. Representative examples include fluoxetine (brand name: Prozac), paroxetine (brand name: Seroxate), and sertraline (brand name: Zoloft), which are widely approved due to their clinical efficacy. However, the aforementioned drugs also have side effects such as whole-body fatigue, sexual dysfunction and insomnia. Administration of antidepressants was reported to typically activate a serotonin receptor by increasing serotonin levels, leading to an activation of protein kinase A (PKA) that is downstream of the serotonin receptor and eventually increases in protein levels of cAMP response element-biding (CREB), brain-derived neurotrophic factor (BDNF) and its receptor, trkB. These increased protein levels are considered to indicate effective actions of antidepressants in molecular levels (J. of Psychosomatic Research 53, 687-697 (2002) ). In addition, the administration of antidepressants restores to normal levels decreased concentrations of cortisol and interleukin-2 (IL-2) and decreased cell numbers of white blood cell (WBC) and lymphocytes, all of which are representative responses of individuals with depression, thereby providing a normal immune system (Ann NY Acad Sci. 917, 478-487 (2000)). These effects may be another the rapeutic effect of antidepressants.
Recently, in the Western countries, medicinal herbal extracts have been recognized for their therapeutic effects and studied. With regard to depression, extracts of Hypericum perforatum (known also as St. John's wort) have been studied (Neuropharmacology, 1999, 21 (2), 247-257; Cochrane Database Syst Rev, 2000, (2), CD000448 ; Drugs Aging, 2000, 16 (3), 189-197).
According to a report that compared a Hypericum perforatum extract with imipramine for therapeutic efficacy on depression, the Hypericum perforatum extract has similar efficacy to imipramine in treating depression and has fewer side effects (BMJ, 2000, 321,536-539). Also, the Hypericum perforatum extract has the potential to inhibit the activities of human cytochrom P450 enzymes (J Pharmacol Exp Ther, 2000, 294(1), 88-95).
The Hypericum perforatum extract contains a large number of structurally different compounds that directly or indirectly affect the central nervous system (CNS). That is, the Hypericum perforatum extract contains bioactive compounds, such as hypericin and hyperforin, and dimeric flavors, which are known to have antidepressive and apprehension-removing effects in animals and humans.
The action mechanisms of the constituents of Hypericum perforatum are as follows. Hypericin is proved to have the antidepressive effect in the presence of dimeric procyanidins contained in the Hypericum perforatum extract (Regensburg, Germany, V. Butterwecke et. al.,45th Annual Congress of the Society for Medicinal Plant Research, 1997, Abstract No. 011). Hyperforin increases 5-HT (serotonin) levels in the hypothalamus and hippocampus, indicating that the antidepressive effect of hyperforin is associated with the serotonergic system (J Pharm Pharmacol, 2001, 53 (5), 583-600; Pharmacopsychiatry, 2000, 33(2), 60-65). However, about 20% of depression patients are not treated with conventional antidepressants, and recently developed antidepressants such as SSRI have fewer side effects than other antidepressants, but they are still not negligible.
On the other hand, various depression animal models have been tried in the development process of antidepressants for treating depression. Strong stimuli such as intense foot-shock, cold water immersion and 48 h food/water deprivation were initially preferred, but, recently, preferred methods are to use weak repetitive stresses better capable of mimicking usual activities of modern people experiencing weak prolonged chronic stresses (Psychopharmacology, 1984, 83, 1-16). Among the recent methods, a chronic mild stress (hereinafter, referred to simply as “CMS”) model, suggested by Willner et al., has been approved as an excellent animal model of depression having reliability and validity (Neuroscience and Biobehavial Review, 1981, 5, 231-246; TIPS, 1991, 12, 131-136).
“Mildly stressed rats” means that, when CMS-induced behavioral changes are observed for a prolonged administration period of weeks, the behavioral changes do not occur habitually, or habitual changes occur within a constant limitation (Psychopharmacology, 1997, 134, 319-320). In general experiments, a variety of chronic weak stressors, such as overnight illumination, periods of food and/or water deprivation, cage tilt and change of cage mate, are used (Psychopharmacology, 1997, 134, 319-320). Repeated exposure of white rats to such stressors results in a significant decrease in consumption of a sucrose solution, which is comparable to anhedonia, the representative symptom of depression of white rats. Upon no appropriate treatment, such decrease in consumption of a sucrose solution is known to last for several weeks after withdrawal of a CMS procedure. Many antidepressants have been approved that they have effects of recovering the reduced sucrose intake induced by the CMS procedure to an original level (Psychopharmacology, 1992, 109, 433-438).
On the other hand, Nelumbinis Semen is the skinned ripe seed of lotus (Nelumbo nucifera), which has a green core. Nelumbinis Semen has no smell and a sweet, fresh and slightly astringent taste.
Nelumbinis Semen contains a large quantity of starch and raffinose sugar, and is known to have the therapeutic effects of strengthening the spleen and stomach, alleviating insomnia, whitening the skin, relieving inflammation and healing wounds in the skin. However, to date, there is no report of its ability to alleviate depression symptoms.